NLRP3 at the crossroads between immune/inflammatory responses and enteric neuroplastic remodelling in a mouse model of diet-induced obesity

Type Article

Journal Article


C. Pellegrini; M. Fornai; L. Benvenuti; R. Colucci; V. Caputi; P. Palazon-Riquelme; M. C. Giron; A. Nericcio; F. Garelli; V. D'Antongiovanni; C. Segnani; C. Ippolito; M. Nannipieri; G. Lopez-Castejon; P. Pelegrin; G. Haskó; N. Bernardini; C. Blandizzi; L.

Year of publication



Br J Pharmacol








BACKGROUND AND PURPOSE: Enteric neurogenic/inflammation contributes to bowel dysmotility in obesity. We examined the role of NLRP3 in colonic neuromuscular dysfunctions in mice with high-fat diet (HFD)-induced obesity. EXPERIMENTAL APPROACH: Wild-type C57BL/6J and NLRP3-KO (Nlrp3(-/-) ) mice were fed with HFD or standard diet for 8 weeks. The activation of inflammasome pathways in colonic tissues from obese mice was assessed. The role of NLRP3 in in vivo colonic transit and in vitro tachykininergic contractions and substance P distribution was evaluated. The effect of substance P on NLRP3 signalling was tested in cultured cells. KEY RESULTS: HFD mice displayed increased body and epididymal fat weight, cholesterol levels, plasma resistin levels and plasma and colonic IL-1β levels, colonic inflammasome adaptor protein apoptosis-associated speck-like protein containing caspase-recruitment domain (ASC) and caspase-1 mRNA expression and ASC immunopositivity in macrophages. Colonic tachykininergic contractions were enhanced in HFD mice. HFD NLRP3(-/-) mice developed lower increase in body and epididymal fat weight, cholesterol levels, systemic and bowel inflammation. In HFD Nlrp3(-/-) mice, the functional alterations of tachykinergic pathways and faecal output were normalized. In THP-1 cells, substance P promoted IL-1β release. This effect was inhibited upon incubation with caspase-1 inhibitor or NK(1) antagonist and not observed in ASC(-/-) cells. CONCLUSION AND IMPLICATIONS: In obesity, NLRP3 regulates an interplay between the shaping of enteric immune/inflammatory responses and the activation of substance P/NK(1) pathways underlying the onset of colonic dysmotility. Identifying NLRP3 as a therapeutic target for the treatment of bowel symptoms related to obesity.